IL-1beta signals through the EGF receptor and activates Egr-1 through MMP-ADAM

• Published in: PloS one 2012-07, Vol.7 (7), p.e39811-e39811
• Main Authors: Sanchez-Guerrero, Estella, Chen, Elya, Kockx, Maaike, An, Si-Wei, Chong, Beng H, Khachigian, Levon M
• Format: Article
• Language: English
• Subjects: ADAM protein; ADAM Proteins - antagonists & inhibitors; ADAM Proteins - metabolism; Animals; Atherosclerosis; Biology; Cytokines; Dipeptides - pharmacology; DNA binding proteins; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; EGR-1 protein; Embryo fibroblasts; Embryos; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Fibroblasts; Gene expression; Genes; Helicobacter pylori; Humans; Interleukin 1; Interleukin 1 receptors; Interleukin-1beta - metabolism; Interleukin-1beta - pharmacology; Ischemia; Kinases; Ligands; Matrix Metalloproteinases - metabolism; Medicine; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Pathogenesis; Pharmacology; Phosphorylation; Polyclonal antibodies; Protein-tyrosine kinase; Quinazolines - pharmacology; Rats; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; siRNA; Tyrosine; Tyrphostins - pharmacology; Veins & arteries; Wound healing; Zinc; Zinc finger proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039811

The immediate-early gene Egr-1 controls the inducible expression of many genes implicated in the pathogenesis of a range of vascular disorders, yet our understanding of the mechanisms controlling the rapid expression of this prototypic zinc finger transcription factor is poor. Here we show that Egr-1 expression induced by IL-1beta is dependent on metalloproteinases (MMP) and a disintegrin and a metalloproteinase (ADAM). Pharmacologic MMP/ADAM inhibitors and siRNA knockdown prevent IL-1beta induction of Egr-1. Further, IL-1beta activates Egr-1 via the epidermal growth factor receptor (EGFR). This is blocked by EGFR tyrosine kinase inhibition and EGFR knockdown. IL-1beta induction of Egr-1 expression is reduced in murine embryonic fibroblasts (mEFs) deficient in ADAM17 despite unbiased expression of EGFR and IL-1RI in ADAM17-deficient and wild-type mEFs. Finally, we show that IL-1beta-inducible wound repair after mechanical injury requires both EGFR and MMP/ADAM. This study reports for the first time that Egr-1 induction by IL-1beta involves EGFR and MMP/ADAM-dependent EGFR phosphorylation.